College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.
Key Laboratory of Animal Vaccine Development, Ministry of Agriculture, Guangzhou, China.
Biofactors. 2021 Sep;47(5):852-864. doi: 10.1002/biof.1771. Epub 2021 Jul 28.
Fibrosis is a pathological process characterized by abnormal activation of fibroblasts with increased synthesis of extracellular matrix components, including collagens. It may lead to loss of proper tissue architecture and organ function in clinical diseases such as systemic sclerosis and liver fibrosis. Excess accumulation of collagens is considered the primary indicator of fibrosis. Notch signaling has been reported to be involved in the fibrosis of many different organs, including the liver. Our previous study showed that the uterine-specific over-activation of canonical Notch1 signaling in the mouse uterus (Pgr Rosa26 , OEx) results in complete infertility as a consequence of multiple developmental and physiological defects, together with increased collagen accumulation evidenced by Masson's staining. In this study, we further detected expressions of all 44 collagen genes in these Notch1 gain-of-function transgenic mice and found that 18 collagens have been largely affected. In another aspect, using an intrauterine adhesion model (IUA), we mimicked fibrosis in the mouse uterine. The results suggested that Notch receptors were upregulated only 3 days after induction, and most of the fibril-forming collagen began to upregulate 6 days after the surgery. Furthermore, when induced IUA in the N1ICD-OEx mice, the expression of collagens and fibrosis levels were significantly enhanced. At last, as a Notch signaling inhibitor, the γ-secretase inhibitor N-[N-(3,5-difl uorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) pretreatment could alleviate the expression of collagens and the symptoms of fibrosis. These results demonstrate that Notch signaling may play a role in upregulating collagens expression in endometrial fibrosis and might be a potential target of fibrosis therapy in the endometrium.
纤维化是一种病理过程，其特征为成纤维细胞异常激活，细胞外基质成分（包括胶原）合成增加。在系统性硬化症和肝纤维化等临床疾病中，它可能导致组织结构和器官功能丧失。胶原过度积累被认为是纤维化的主要指标。 Notch 信号通路已被报道参与许多不同器官的纤维化，包括肝脏。我们之前的研究表明，在小鼠子宫中（Pgr Rosa26, OEx）特异性过激活经典 Notch1 信号通路，会导致多种发育和生理缺陷，以及 Masson 染色证实胶原积累增加，从而导致完全不孕。在这项研究中，我们进一步检测了这些 Notch1 功能获得转基因小鼠中所有 44 种胶原基因的表达，发现其中 18 种胶原受到了很大影响。另一方面，我们使用了宫内粘连模型（IUA），模拟了小鼠子宫中的纤维化。结果表明，Notch 受体在诱导后仅 3 天就上调，并且大多数纤维形成胶原在手术后 6 天开始上调。此外，当在 N1ICD-OEx 小鼠中诱导 IUA 时，胶原的表达和纤维化水平显著增强。最后，作为 Notch 信号通路抑制剂，γ-分泌酶抑制剂 N-[N-(3,5-二氟苯乙酰基)-L-丙氨酰]-S-苯甘氨酸叔丁酯（DAPT）预处理可以减轻胶原的表达和纤维化的症状。这些结果表明，Notch 信号通路可能在子宫内膜纤维化中上调胶原的表达中发挥作用，并且可能成为子宫内膜纤维化治疗的潜在靶点。
